Identification of chemokine receptors as potential modulators of endocrine resistance in estrogen receptor positive breast cancers (Breast Cancer Research)

IntroductionEndocrine therapies target estrogenic stimulation of breast cancer (BC) growth but resistance remains problematic. Our aims were 1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term estrogen deprivation (LTED); 2) to assess the clinical value of selected genes in public clinical data sets; 3) to determine the impact of targeting these genes with novel agents. Methods: Gene expression and Ki67 data were available from 69 postmenopausal women with estrogen receptor positive (ER+) early BC, at baseline and 2-weeks post anastrazole treatment and from cell lines adapted to LTED. Functional consequence of target genes on proliferation, ER-mediated transcription and downstream cell signaling were assessed. Results: Intersection of genes predicting for a poor change in Ki67, with those up-regulated in LTED cells, identified 32 genes strongly correlated with poor antiproliferative response, which were associated with inflammation/immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild-types (wt), CXCR7 but not CXCR4 associated with reduced relapse free survival in ER?+?BC patients. In wt-SUM44, wt-MCF7 and their LTED derivatives, siCXCR4 had no specific effect on their proliferation. In contrast, siCXCR7 and CCX733, a CXCR7 antagonist specifically suppressed proliferation of MCF7-LTED cells. SiCXCR7 suppressed proteins associated with G1-S transition and inhibited ER-transactivation in MCF7-LTED but not wt-MCF7 by impeding association between ER and proline, glutamic acid and leucine rich protein 1 (PELP1), an ER coactivator. Conclusion: These data highlight CXCR7 as a potential therapeutic target, warranting clinical investigation in endocrine resistant BC.